A JAK/STAT-Pdk1-S6K axis bypasses systemic growth restrictions to promote regeneration

Inflammation triggers systemic signals that induce growth restrictions in distant organs, a process well characterized in tumor cachexia. While mechanisms allowing tumors to circumvent these systemic growth restrictions have been established, the physiological processes that overcome inflammation-induced growth restrictions during regeneration remain largely unexplored. In our study, we use a model of tissue inflammation and regeneration in developing Drosophila imaginal discs to dissect key metabolic and signaling adaptations that, in physiological settings, both induce and overcome systemic growth restrictions. We find that expression of eiger , the Drosophila TNF-α homolog, induces systemic insulin restriction, as evidenced by reduced expression of dILP2 and dILP5 , as well as elevated nuclear dFOXO, and reduced protein translation and proliferation in peripheral tissues. Proliferating cells overcome systemic insulin restriction by upregulating Pdk1, which is both necessary and sufficient to promote phosphorylation of ribosomal protein S6 and protein translation via an Insulin/Akt-independent mechanism. We further demonstrate that JAK/STAT signaling acts upstream to increase Pdk1 levels, delineating a novel JAK/STAT-Pdk1-S6K axis essential for regenerative proliferation. The upregulation of amino acid transporters in the proliferative domain further suggests that regenerating cells preferentially import amino acids, fueling mTORC1 activation. Similar metabolic signatures are observed in a Drosophila Ras ^V12 , scrib tumor model, suggesting that tumors may co-opt these metabolic pathways to sustain growth in an insulin-restricted environment. Our findings reveal a specialized metabolic program that integrates systemic nutrient mobilization with local metabolic reprogramming, with important implications for understanding of physiological tissue repair but also pathologies such as chronic wounds and cancer.